Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages

ObjectivesTo investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.MethodsWe studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.ResultsLXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.ConclusionsWe identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.

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Using integrative lipid systems biology to understand the role of Liver X receptors (LXRs) in male reproduction

Endocrine Abstracts ◽

10.1530/endoabs.59.oc2.5 ◽

2018 ◽

Author(s):

Sheba Jarvis ◽

Lee Gethings ◽

Raffaella Gadeleta ◽

Emmanuelle Claude ◽

Robert Winston ◽

...

Keyword(s):

Systems Biology ◽

Male Reproduction ◽

Liver X Receptors ◽

X Receptors

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Faculty Opinions recommendation of Role of Atg5-dependent cell death in the embryonic development of Bax/Bak double-knockout mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727681479.793532876 ◽

2017 ◽

Author(s):

Sharad Kumar ◽

Donna Denton

Keyword(s):

Cell Death ◽

Embryonic Development ◽

Knockout Mice ◽

Double Knockout ◽

Dependent Cell

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Role of the microbiota in ileitis of a mouse model of inflammatory bowel disease—Glutathione peroxide isoenzymes 1 and 2‐double knockout mice on a C57BL background

MicrobiologyOpen ◽

10.1002/mbo3.1107 ◽

2020 ◽

Vol 9 (10) ◽

Author(s):

Fong‐Fong Chu ◽

R. Steven Esworthy ◽

Binghui Shen ◽

James H. Doroshow

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Model ◽

Knockout Mice ◽

Bowel Disease ◽

Double Knockout ◽

Inflammatory Bowel

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Minireview: Liver X Receptor β: Emerging Roles in Physiology and Diseases

Molecular Endocrinology ◽

10.1210/me.2008-0398 ◽

2009 ◽

Vol 23 (2) ◽

pp. 129-136 ◽

Cited By ~ 33

Author(s):

Chiara Gabbi ◽

Margaret Warner ◽

Jan-Åke Gustafsson

Keyword(s):

Current Knowledge ◽

Large Family ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Liver X Receptors ◽

Cholesterol Accumulation ◽

Reverse Transport ◽

X Receptors ◽

Lateral Sclerosis

Abstract Liver X receptors, LXRα and LXRβ, are nuclear receptors belonging to the large family of transcription factors. After activation by oxysterols, LXRs play a central role in the control of lipid and carbohydrate metabolism as well as inflammation. The role of LXRα has been extensively studied, particularly in the liver and macrophages. In the liver it prevents cholesterol accumulation by increasing bile acid synthesis and secretion into the bile through ATP-binding cassette G5/G8 transporters, whereas in macrophages it increases cholesterol reverse transport. The function of LXRβ is still under investigation with most of the current knowledge coming from the study of phenotypes of LXRβ−/− mice. With these mice new emerging roles for LXRβ have been demonstrated in the pathogenesis of diseases such as amyotrophic lateral sclerosis and chronic pancreatitis. The present review will focus on the abnormalities described so far in LXRβ−/− mice and the insight gained into the possible roles of LXRβ in human diseases.

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Polyamine homeostasis in arginase knockout mice

AJP Cell Physiology ◽

10.1152/ajpcell.00393.2006 ◽

2007 ◽

Vol 293 (4) ◽

pp. C1296-C1301 ◽

Cited By ~ 14

Author(s):

Joshua L. Deignan ◽

Justin C. Livesay ◽

Lisa M. Shantz ◽

Anthony E. Pegg ◽

William E. O'Brien ◽

...

Keyword(s):

Knockout Mice ◽

Polyamine Metabolism ◽

Mrna Levels ◽

Ornithine Aminotransferase ◽

Double Knockout ◽

Mammalian Tissues ◽

Knockout Animals ◽

Regulatory Functions ◽

Arginase I

The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.

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Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

PLoS Biology ◽

10.1371/journal.pbio.3000948 ◽

2020 ◽

Vol 18 (12) ◽

pp. e3000948

Author(s):

Laura Bousset ◽

Amandine Septier ◽

Julio Bunay ◽

Allison Voisin ◽

Rachel Guiton ◽

...

Keyword(s):

Chronic Inflammation ◽

Nuclear Receptors ◽

Metabolic Disorders ◽

Androgen Deprivation ◽

Liver X Receptors ◽

Phenotypic Alteration ◽

Prostate Cells ◽

Common Causes ◽

X Receptors

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

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Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins

Scientific Reports ◽

10.1038/s41598-019-53317-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Norbert Bencsik ◽

Szilvia Pusztai ◽

Sándor Borbély ◽

Anna Fekete ◽

Metta Dülk ◽

...

Keyword(s):

Dendritic Spine ◽

Knockout Mice ◽

Hippocampal Neurons ◽

Pain Perception ◽

Hippocampal Slices ◽

Scaffold Proteins ◽

Double Knockout ◽

Learning Abilities ◽

Spine Morphology

AbstractCASK-interactive proteins, Caskin1 and Caskin2, are multidomain neuronal scaffold proteins. Recent data from Caskin1 knockout animals indicated only a mild role of Caskin1 in anxiety and pain perception. In this work, we show that deletion of both Caskins leads to severe deficits in novelty recognition and spatial memory. Ultrastructural analyses revealed a reduction in synaptic profiles and dendritic spine areas of CA1 hippocampal pyramidal neurons of double knockout mice. Loss of Caskin proteins impaired LTP induction in hippocampal slices, while miniature EPSCs in dissociated hippocampal cultures appeared to be unaffected. In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines. Chemically induced LTP (cLTP) mediated enlargement of spine heads was augmented in the knockout mice and was not influenced by Caskin1. Immunocytochemistry and immunoprecipitation confirmed that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex. Phosphorylation of AMPA receptors was specifically altered by Caskin deficiency and was not elevated by cLTP treatment further. Taken together, our results prove a previously unnoticed postsynaptic role of Caskin scaffold proteins and indicate that Caskins influence learning abilities via regulating spine morphology and AMPA receptor localisation.

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